The conventional target centric model of drug discovery is pinned under the weight of prior success and the traditional problems of safety and efficacy for new molecules. An alternative to target centric drug development is to shift focus to the pathways that mediate both biology and pathophysiology. This method has the advantage of not requiring a priori knowledge of the small molecule target, but also comes with it several challenges including target determination. We suggest extending this notion more broadly across the drug discovery process using quantitative network structure-activity relationships (QNSAR), and discuss the steps necessary to test the hypothesis that systems biology approaches can be used to improve the drug discovery process.